tbuckley/cabot-search huggingface dataset:
Safety and immunogenicity of the FINLAY-FR-1A vaccine in COVID-19 convalescent participants: an open-label phase 2a and double-blind, randomised, placebo-controlled, phase 2b, seamless, clinical trial
Authors: Rolando Ochoa-Azze, Arturo Chang-Monteagudo, Yanet Climent-Ruiz, Consuelo Macías-Abraham, Carmen Valenzuela-Silva, María de los Ángeles García-García, Yanet Jerez-Barceló, Yenisey Triana-Marrero, Laura Ruiz-Villegas, Luis Dairon Rodríguez-Prieto, Pedro Pablo Guerra-Chaviano, Belinda Sánchez-Ramírez, Tays Hernández-García, Ivette Orosa-Vázquez, Marianniz Díaz-Hernández, Fabrizio Chiodo, Andrea Calcagno, Valeria Ghisetti, Mireida Rodríguez-Acosta, Enrique Noa-Romero, Juliet Enríquez-Puertas, Darién Ortega-León, Irinia Valdivia-Álvarez, Aurora Delahanty-Fernández, Ariel Palenzuela-Díaz, Laura Rodríguez-Noda, Raúl González-Mugica, Yury Valdés-Balbín, Dagmar García-Rivera, Vicente Verez-Bencomo
Journal: The Lancet Respiratory Medicine (2022)
15 years of experience of an oncogenetics service in the northeast of Brazil.
Authors: Thamara Melo Ferreira, Maria Betania Toralles, Taisa Lopes, Pollyanna Carozo Oliveira, Ivana Lucia de Oliveira Nascimento, Juliana Côrtes, Thais Ferreira Bomfim-Palma, Roberto JOSE MEYER Nascimento, Juliana LIMA GOMES Rodrigues
Journal: Journal of Clinical Oncology (2022)

e22522 Background: The Oncogenetics service at the Federal University of Bahia was implemented in 2007 and since then has been offering pre- and post-test genetic counseling for cancer susceptibility genes, mainly tumors associated with King's syndrome in the population of the state of Bahia. This is a mixed population of about 80% of African ancestry. Methods: Between the years 2007 to 2021, 462 probands and their families have already been evaluated by NGS analysis, Sanger sequencing. Large rearrangements were detected by multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 and BRCA2 genes. Results: The mean age at diagnosis was 41 years. Pathogenic/probably pathogenic mutations were founded in 118 patients: 67 had breast cancer, 09 with ovarian cancer, 26 with more than one tumor, 15 without cancer, and 01 with another tumor type. Most of the pathogenic variants were located in the BRCA1 gene (27 variants), the two most frequent variants being: c.211G &gt; A (13 probands) and c.3331_3334delCAAG (18 probands), both of Iberian origin. Of patients with mutation, 9.8% had large rearrangements in BRCA1 and 11.5% in BRCA2. Bilateral breast cancer appears predominantly in patients with BRCA1 (4) and BRCA2 (1) variants. In this study, only two mutations in BRCA described as of African origin were found in two patients. Other pathogenic mutations appear in ATM, BARD1, BRIP1, CDH1, CHEK2, FAM175A, FANCM, MSH6, NBN, NF2, PALB2, RAD51, SDHB, SLX4, and TP53 genes. Variants of uncertain significance were identified in 71 patients. Conclusions: The population of the state of Bahia has a peculiar mutational profile, containing mutations that are not very frequent in other regions of the country. Despite being a population with high African ancestry, most mutations are of European origin.
NFB-17. "Optic Pathway findings in children with Neurofibromatosis type-1 (NF-1)
Authors: Kleoniki Roka, Eleftheria Kokkinou, Maria Gavra, Efthymia Tsina, Konstantina Mparka, Georgios Zarafonitis, Konstantina Kosma, Periklis Makrythanasis, Maria Tzetis, Maria Chasiotou, Christina Kanaka-Gantenbein, Roser Pons, Antonis Kattamis
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND/OBJECTIVES:Optic-pathway-glioma(OPG) represents the most common central-nervous tumor in children with neurofibromatosis type-1(NF1), occurring at an incidence of 15-20%. It is estimated that 1/3 of NF1 patients(pts) with OPG will need treatment. DESIGN-METHODS:We performed a retrospective-review of all NF1-pts examined in the First Hellenic Multidisciplinary-Clinic – Center of Expertise for Neurocutaneous-disorders. Gender, age, MRI-radiological and ophthalmological findings, presence of OPG, management and outcome were analyzed. RESULTS:Since the establishment of the Clinic in 2016, 198pts with clinical diagnosis of NF1 based on NIH1988-criteria were evaluated and of them, 165(73 females, median age:5.5y, range:0.3-17.1y), who had imaging studies were included in this analysis. Eighty three pts(50.3%) had NF1-positive genetic-testing and 45NF1-family-history(27.3%). Imaging-findings from optic pathway were found in 55/165pts(28females). Percentage of pts with findings were 51.7% for &amp;lt;3y, 45.4% for 3-5y, 34.7% for 5-10y and 8.5% for &amp;gt;10y, respectively. The median age of their first brain-MRI imaging was 2.82y. Upon 1stMRI-imaging, 70.9% presented thickness of the optic nerves(ON)(25,4%bilateral, 20% optic chiasm,18.1% right ON, 10.0% left ON), 14.5%ON-tortuosity, 38.1%OPG(43,5% in the optic-chiasm) and 34.5% contrast enhancement. Of notice, 14pts presented an OPG after a median follow-up time of 1.79y. According to LGG2004-protocol indications for treatment, only 15/55pts had to be treated(27,2%, 5pts with family history, 33.3% between 5-10y). Severe vision-loss with need for immediate start of treatment upon 1stMRI imaging was found in 4pts, of whom 75% had family-history and first evaluation after the 5th year of age. Of notice, only 2pts&amp;lt;3y had to receive treatment, one with family-history and one with symptoms(diencephalic syndrome). CONCLUSIONS: Pts with NF1 should be followed by a multidisciplinary-team. Management should be individualized and imaging-studies can be limited to patients at high-risk. Positive family-history may be a negative prognostic factor for OP lesions.
DASL-HiCaP: Darolutamide augments standard therapy for localized very high-risk cancer of the prostate (ANZUP1801)—A randomized phase 3, double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation.
Authors: Tamim Niazi, Sean Matthew McBride, Scott Williams, Ian D. Davis, Martin R. Stockler, Andrew James Martin, Karen Bracken, Felicia Roncolato, Lisa Horvath, Shomik Sengupta, Jarad Martin, Tee Lim, Simon Hughes, Raymond S. McDermott, James W.F. Catto, Paul J. Kelly, Wendy R. Parulekar, Scott Carlyle Morgan, Ricardo A. Rendon, Christopher Sweeney
Journal: Journal of Clinical Oncology (2022)

TPS5103 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analog (LHRHA), is standard of care for men with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT in the setting of either primary definitive therapy, or salvage therapy for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind trial for men planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by: RP; use of adjuvant docetaxel; pelvic nodal involvement. 1100 participants will be randomized to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomization. Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival (ICECaP-validated), with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353.
Updates in Screening Recommendations for Colorectal Cancer
Authors: Reid M. Ness
Journal: Journal of the National Comprehensive Cancer Network (2022)

In the past 2 years, several significant changes have been made to the NCCN Guidelines for Colorectal Cancer (CRC) Screening. The age for initiation of screening average-risk adults has been lowered from age 50 to 45 years—without differentiation by age and race—and from age50 to 45 years for those with second- and third-degree relatives with CRC. For several groups, surveillance intervals have been changed. Patients with 1 or 2 low-risk adenomas at index colonoscopy, on the other hand, can now wait 10 years rather than 5 to 7 years between surveillance examinations. The first surveillance examination following resection of large adenomas or sessile serrated polyps (SSPs) with unfavorable-risk characteristics or that were removed piecemeal should now occur at 6 months. For patients with ≥10 adenomas and SSPs on a single colonoscopy, time to first surveillance was lowered to 1 year.
Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC, RATIONALE 302): Impact on health-related quality of life (HRQoL).
Authors: Eric Van Cutsem, Ken Kato, Jaffer A. Ajani, Lin Shen, Tianyu Xia, Ningning Ding, Lin Zhan, Gisoo Barnes, Sung-Bae Kim
Journal: Journal of Clinical Oncology (2022)

e16095 Background: RATIONALE 302 was a global phase 3 study (NCT03430843) that investigated tislelizumab (TIS) compared with investigator-chosen chemotherapy (ICC) as second-line treatment for patients (pts) with advanced or metastatic ESCC, in which TIS demonstrated a significant and clinically meaningful improvement in overall survival hazard ratio (HR = 0.70 [95% CI 0.57–0.85], P=0.0001), and a favorable safety profile compared with ICC. Here we assess the HRQoL of pts receiving TIS vs ICC in a pt population that usually experiences HRQoL deterioration. Methods: Adults with advanced or metastatic ESCC whose disease progressed following prior systemic therapy were randomized 1:1 to either TIS 200 mg IV every 3 weeks or ICC (paclitaxel, docetaxel, or irinotecan). HRQoL was measured using the global health status/quality of life (GHS/QoL), physical functioning, and fatigue scores from EORTC QLQ-C30 and the dysphagia, reflux, eating, and pain scores from the EORTC QLQ-OES18 from screening through Cycle 6 or until treatment discontinuation (whichever occurs first). Least-squares mean score change from baseline to Cycles 4 and 6 in HRQoL scores was assessed using a mixed model for repeated measurements. Time to deterioration (TTD) for the GHS/QoL score and the symptom scales of the QLQ-OES18 was examined using the Kaplan-Meier method. Results: Overall, 512 pts (median age 62) were randomized to TIS (n=256) or ICC (n=256). Compared with ICC, TIS-treated pts had stable GHS/QoL and fatigue scores as well as less decline in physical functioning at Cycles 4 and 6 (table). Except for pain, the TIS arm experienced less OES18 symptoms relative to baseline than the ICC arm. TTD analysis showed pts in TIS arm were at lower risk of worsening dysphagia (HR = 0.76 [95% CI 0.53, 1.07], P=0.0562) compared with ICC. Conclusions: The analysis showed that ESCC pts treated with TIS in the second line had a longer maintenance of HRQoL compared to pts treated with ICC. These results, along with improved survival and favorable safety profile, suggest TIS represents a potential new second-line treatment option for pts with advanced or metastatic ESCC. Clinical trial information: NCT03430843. [Table: see text]
Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC).
Authors: D. Ross Camidge, Jair Bar, Hidehito Horinouchi, Jonathan W. Goldman, Fedor Vladimirovich Moiseenko, Elena Filippova, Irfan Cicin, Penelope Ann Bradbury, Nathalie Daaboul, Pascale Tomasini, Tudor-Eliade Ciuleanu, David Planchard, Mor Moskovitz, Nicolas Girard, Janet Yikai Jin, Martin Dunbar, Ellen Bolotin, Jim Looman, Christine Ratajczak, Shun Lu
Journal: Journal of Clinical Oncology (2022)

9016 Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to &lt;50% 3+) and for the SQ cohort as ≥75% 1+ by IHC. The planned enrollment was up to approximately 150 pts in Stage 1 and 160 pts in Stage 2. Teliso-V was dosed at 1.9 mg/kg IV Q2W. The primary endpoint is objective response rate (ORR) by independent central review. Secondary endpoints include duration of response (DOR). Results: As of data cutoff (27 May 2021), 136 pts were treated with Teliso-V; 122 were evaluable for ORR. ORR was 36.5% in the NSQ EGFR WT cohort (52.2% in c-Met high group and 24.1% in c-Met intermediate group), but was modest in the NSQ EGFR mutant and SQ cohorts. Efficacy data in groups/cohorts are in the Table. The most common any-grade adverse events (AEs) were peripheral sensory neuropathy (25.0%), nausea (22.1%), and hypoalbuminemia (20.6%). Grade 5 AEs considered possibly related to Teliso-V occurred in 2 pts (sudden death and pneumonitis in 1 pt each in the SQ cohort). Conclusions: Teliso-V demonstrated a promising ORR in pts with previously treated c-Met OE NSQ EGFR WT NSCLC; this cohort is currently expanding in Stage 2. ORR was modest in the cohorts of pts with c-Met OE NSQ EGFR mutant NSCLC and with c-Met OE SQ NSCLC; both cohorts have now met the protocol-specified stopping criteria and are no longer enrolling. The safety profile observed was consistent with IA3. Clinical trial information: NCT03539536. [Table: see text]
Using nucleosome levels, copy number alterations, and DNA methylation to profile disease state through liquid biopsy.
Authors: Sarah Harrison, Shane G. Poplawski, Shari Orlanski, Melvin Wei, Brandi Atteberry, Benjamin P. Berman, Terry Kelly
Journal: Journal of Clinical Oncology (2022)

e15014 Background: Nucleosomes are the repeating unit of chromatin that contain important signals for proper genomic function and transcriptional activity. Upon cell death, chromatin is fragmented, and nucleosomes are released into circulation and thus, detectable in liquid biopsy. Cell death naturally occurs over time and increases in a variety of diseases resulting in elevated levels of circulating nucleosomes and the genetic and epigenetic signatures they carry. These signatures contain important information about the cells from which they were derived, as well as the reason for them being in circulation. Methods: We measured circulating nucleosome levels, using Volition’s Nu.Q H3.1 sandwich ELISA across a healthy cohort spanning 40-85 years of age as well as patients whom had been diagnosed with Non-Hodgkin's Lymphoma (NHL), some of which were untreated and others that had undergone treatment. Additionally, to demonstrate that the correlation between nucleosome (Nu.Q) levels and copy number alterations is specific to cancer, we assessed the genomic integrity of an NHL sample with a Nu.Q level of 744 ng/ml and a sepsis sample with Nu.Q level of 3,281 ng/ml using low coverage Oxford Nanopore whole genome sequencing to identify genomic amplifications and deletions. We further used cell type specific methylation patterns to identify the cell of origin of cfDNA in each sample. Results: Importantly, we found no significant correlation between nucleosome level and age in our healthy cohort (R 2 = 0.0004; 40-49: N = 10, mean = 39 ng/ml; 50-59: N = 10, mean = 18 ng/ml; 60-69: N = 10, mean = 35 ng/ml; 70-79: N = 15, mean = 34 ng/ml; 80-85: N = 5, mean = 32 ng/ml). We did however find elevated nucleosome levels in untreated NHL patients (N = 4, mean 646 ng/ml) and that nucleosome levels in NHL patients that had undergone treatment were reduced (N = 29, mean = 180 ng/ml). Using copy number changes, we found that the fraction of cfDNA estimated to be derived from the tumor in the NHL sample was 54% and were able to detect amplifications in chromosomes 10, 11 and 18 and deletions in chromosomes 1, 8, 17, 18 and 23, whereas we found no copy number alterations present in the cfDNA sample derived from a sepsis patient and a tumor fraction of 0. Furthermore, using cell type specific methylation patterns to deconvolute the data we found that a large fraction of the cfDNA in the NHL sample was derived from B-cells consistent with the NHL sample being of B-cell origin whereas we determined that the cell of origin of the cfDNA in the sepsis sample was Neutrophils. Conclusions: This data shows that nucleosome levels, as measured by Nu.Q, can be used in conjunction with shallow sequencing and DNA methylation profiles to define tumor fraction and cell of origin in liquid biopsy.
Molecular alterations associated with rapid progression following CDK4/6 inhibitors (CDKi) in metastatic hormone receptor–positive breast cancer (mHRBC).
Authors: Malinda T West, Shaun Goodyear, Andy Kaempf, Thomas Kartika, Jessica Ribkoff, Evthokia Hobbs, Zahi Ibrahim Mitri
Journal: Journal of Clinical Oncology (2022)

1054 Background: Combination of CDKi with endocrine therapy is a key treatment for mHRBC due to survival benefit and favorable safety profile. However, progressive disease inevitably develops and outcomes after CDKi discontinuation (dc) are not well-described. Within our institution, we previously reported clinical characteristics and outcomes for a cohort of 140 mHRBC patients who received CDKi therapy. Median progression-free survival (PFS) and overall survival (OS) post-CDKi dc were 7.0 and 15.4 months, respectively. However, 29% experienced rapid progression or death within 4 months following CDKi dc. Molecular predictors of rapid progression after CDKi are unknown and may help define therapies to improve outcomes. In this study, we sought to identify molecular predictors for rapid disease progression after CDKi dc in mHRBC. Methods: We identified within our cohort 34 patients with mHRBC who progressed on CDKi with next-generation sequencing (NGS) performed on pre-CDKi tissue samples. PFS and OS, measured from CDKi dc, were analyzed with the Kaplan-Meier estimator and log-rank test. Rapid progression was analyzed with logistic regression and Fisher’s exact test to evaluate association between pre-CDKi tumor mutation and rapid progression post-CDKi. Results: NGS of pre-CDKi tumor biopsies found 12 genes ( FGF3, FGF4, FGFR, PIK3CA, PTEN, AKT, RB1, CDKN2A, MYC, CCND1, ESR1, TP53) that were altered in ≥3 of the 34 patients. The six patients (18%) with a PTEN mutation (mut) had a median PFS of 3 months and median OS of 4 mo. In comparison, median PFS and OS of PTEN wild-type (wt) patients were 7 mo. (log-rank p=0.008) and 21 mo. (log-rank p&lt;0.001), respectively. Moreover, those with PTENmut tumors were more likely to experience rapid progression compared to PTENwt (odds ratio = 7.0, 95% CI: 1.1 – 60.5, p=0.048). Notably, in the 10 rapid progression patients with pre-CDKi NGS results, alterations to PI3K pathway constituents were prevalent: PTENmut (40%), FGFRmut (50%), AKTmut (20%) and PIK3CAmut (40%). Conclusions: PI3K pathway alterations are prevalent in mHRBC patients who develop rapid progression post-CDKi dc, with PTENmut being the most significant predictor. These hypothesis-generating findings provide the basis for ongoing investigations to find clinical and molecular biomarkers that can help improve outcomes for mHRBC at risk of rapid progression post-CDKi therapy.[Table: see text]
Robotic versus open kidney transplantation from deceased donors: The first prospective observational study
Authors: R. Campi, A. Pecoraro, V. Li Marzi, A. Tuccio, P. Barzaghi, F. Corti, A. Rivetti, R. Nicoletti, M. Gacci, S. Morselli, A. Sebastianelli, F. Sessa, P. Spatafora, S. Giancane, A. Peris, C.L. Cirami, A. Breda, G. Vignolini, S. Serni
Journal: European Urology (2022)
Ceasing surveillance in low risk non-muscle invasive bladder cancer after only 12 months of being recurrence free is un-safe: A validation study from the Scottish bladder cancer Quality Performance Indicator (QPI) programme
Authors: P. Mariappan, A. Johnston, M. Trail, S. Hamid, G. Hollins, B.A. Dreyer, S. Ramsey, L. Padovani, R. Garau, J. Guerrero Enriquez, H. Simpson, R. Hasan, C. Sharpe, B.G. Thomas, J. Bhatt, I. Ahmad, G.M. Nandwani, A. Chaudhry, A. Boden, R.S. Khan, G. Maresca, K. Dimitropoulos, C. Graham, D. Hendry, S.L. Paramananthan, G. Loy, S.C. Baker, K.M. Grigor, G. Smith
Journal: European Urology (2022)
Inflammatory correlates of the Patient Global Assessment of Disease Activity vary in relation to disease duration and autoantibody status in patients with rheumatoid arthritis
Authors: Serena Bugatti, Ludovico De Stefano, Bernardo D’Onofrio, Andrea Nicrosini, Eleonora Mauric, Michele di Lernia, Garifallia Sakellariou, Ennio Giulio Favalli, Antonio Manzo, Roberto Caporali, Carlomaurizio Montecucco
Journal: Annals of the Rheumatic Diseases (2022)

Objective To investigate the associations between the Patient Global Assessment (PGA) and measures of disease activity in patients with rheumatoid arthritis (RA) in relation to disease duration and autoantibody status. Methods 1412 patients from three independent cohorts were studied: a prospective cohort of 810 patients with early RA followed up for 24 months; a cross-sectional cohort of 210 patients with established RA in low disease activity; a cross-sectional cohort of 401 patients with established RA in moderate-to-high disease activity. Correlations of the PGA were analysed by Pearson’s coefficients and multivariable linear regression at baseline and at months 6, 12 and 24 in the overall populations and after stratification for autoantibody subgroup and remission status (Boolean remission, PGA near remission and non-remission). Results In patients with early RA in non-remission, swollen joints correlated independently with the PGA; the correlation became progressively weaker but persisted at all time points in autoantibody-positive patients (adjusted r=0.30–0.12) but lost significance after month 12 in autoantibody-negative patients. Swollen joints independently correlated with the PGA also in near remission until month 12 (adjusted r=0.18–0.16) in autoantibody-positive patients. No independent correlations of inflammatory variables were instead found in patients with established RA irrespective of disease activity and autoantibody status. Conclusions In the early phases of RA, particularly in autoantibody-positive patients, inflammatory variables directly correlate with the PGA across different disease activity states. The optimal cut-off values of the PGA capable of identifying absence of disease should be better explored in relation to disease duration and autoantibody status.